DNAJC5 was first reported in relation to autosomal dominant adult neuronal ceroid lipofuscinosis (ANCL) in 2011 (Nosková L, et al., PMID: 21820099). This condition is a subtype of neuronal ceroid lipofuscinoses (NCLs), which are progressive neurodegenerative diseases characterized by mental and motor deterioration, epilepsy, ataxia, vision loss, and a reduced life span. The unifying finding in NCL patients is the accumulation, in neurons and many other cell types, of autofluorescent storage material. One characteristic that separates autosomal dominant NCLs from other types of NCLs is the lack of vision loss. There are 13 subtypes of NCLs that are categorized based on the gene that is involved. DNAJC5 is associated with an autosomal dominant adult NCL (ANCL) with onset ranging from mid 20’s to 40’s.
One deletion, one duplication, and two missense variants reported in seven probands from five publications (PMID:21820099, PMID:22235333, PMID:22978711, PMID:31919451, PMID:35462699) were scored in this curation. All reported variants have been functionally studied and shown to have effects on subcellular localization and palmitoylation. Of the seven probands scored, three with p.Leu115Arg (PMID:21820099, PMID:22235333) and two with p.Leu116del (PMID:2297871) were confirmed independent by the differences in flanking haplotypes. Additional reports regarding these two variants were not scored as the haplotype was either not provided or the identity of the family was unclear (PMID:21820099, PMID:22073189, PMID:29506599, PMID:24277206, PMID:22978711). Supporting gene-level experimental evidence includes protein interaction with the depalmitoylating enzyme palmitoyl-protein thioesterase 1 (PPT1) (PMID: 12134079) and a consistent reduction in protein expression in brain samples from patients with two different variants, p.Leu115Arg and p.Leu116del (PMID:21820099, PMID:26659577).
In summary, there is moderate evidence to support the relationship between DNAJC5 and autosomal dominant ANCL. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the Epilepsy GCEP on June 15, 2021. It was reevaluated on January 7, 2025. As a result of this reevaluation additional evidence was added; however, the classification did not change.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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